Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D211/74—Oxygen atoms
  • C07D211/76—Oxygen atoms attached in position 2 or 6
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
  • C07D211/86—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings

Definitions

• novel compounds of the invention are selected from the group consisting of all possible racemic, enantiomeric and diastereoisomeric forms of a compound of the formula ##STR4## wherein E and G together form a group selected from the group: ##STR5## consisting of a) ##STR6## or E is --COOR 3 and G is ##STR7##
• R is selected from the group consisting of hydrogen alkyl of 1 to 6 carbon atoms, alkenyl or alkynyl of 2 to 6 carbon atoms optionally substituted with aryl radicals of 6 to 14 carbon atoms optionally substituted with at least one member of the group consisting of halogen, --OH, --CF 3 , alkoxy of 1 to 6 carbon atoms, --NO 2 , --CN, --NH 2 , or with the radicals selected from the group consisting of free and esterified or salified carboxy, acyl of 1 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, --OH, --NH
• aryl which can be R.
• Y and B is a carbocyclic aryl for R and an optionally substituted carbocyclic or heterocyclic for Y and B.
• an optionally substituted aryl are phenyl, naphthyl, for example 1-naphthyl; indenyl; a saturated or unsaturated heterocyclic of 5, 6 or 7 links containing at least one heteroatom chosen from sulfur, nitrogen and oxygen.
• the heterocyclic contains more than one heteroatom, the heteroatoms of this heterocyclic group can be identical or different.
• aryl examples include thienyls such as Z-thienyl and 3-thienyl, furyl such as 2-furyl, pyridyl such as 3-pyridyl, pyrimdiyl, pyrrolyl, N-substituted pyrrolyl, such as N-methyl pyrrolyl, thiazolyl, isothiazolyl, diazolyl, triazolyl, tetrazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, 3- or 4-isoxazolyl, substituted 3- or 4-isoxazolyl such as 3-aryl-5-methyl isoxazol-4-yl.
• furyl such as 2-furyl
• pyridyl such as 3-pyridyl
• pyrimdiyl pyrrolyl
• N-substituted pyrrolyl such as N-methyl pyrrolyl
• the aryl may be phenyl or halophenyl and examples of condensed heterocyclics containing at least one heteroatom chosen from sulfur, nitrogen and oxygen are benzothienyl such as 3-benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl or purinyl.
• benzothienyl such as 3-benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl or purinyl.
• aralkyl includes an optionally substituted carbocyclic or heterocyclic aryl in which the lower alkyl contains 1 to 4 carbon atoms as benzyl, phenethyl, diphenylmethyl, triphenylmethyl, thienylmethyl such as 2-thienylmethyl, furylmethyl such as furfuryl, pyridylmethyl or pyrrolylmethyl, the aryl and aralkyl being able to contain at least one substituent selected from the group consisting of halogens such as chlorine or bromine as in o-chlorophenyl; hydroxyl; lower alkyl such as methyl, ethyl, or isopropyl or tertbutyl; alkenyl; alkynyl; trihaloalkyl such as trifluoromethyl; trihaloalkylthio such as for example, trifluoromethylthio; trihaloalkyloxy such astrifluoromethyl; cyano; nitro; amino
• carbocyclic which can be represented by A includes cycloalkyl, cycloalkenyl and cycloalkadienyl or an optionally substituted non-aromatic.
• optionally substituted carbocyclices are cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, 1,3-cyclohexadienyl, 1,4-cyclo-hexadienyl, dimethyl-1,3-cyclohexenyl.
• a as a carbocyclic are preferably the optionally substituted cycloalkyls of the formula ##STR9## in which n is an integer from 0 to 4, preferably 2 and 3.
• Cycloalkyl of 3 to 7 carbons for B are preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
• linear or branched alkyl of 1 to 6 carbons includes methyl, ethyl, propyl or isopropyl, but can also be butyl, isobutyl, sec-butyl, tert-butyl or pentyl.
• linear or branched alkenyl of 2 to 6 carbons includes vinyl, allyl, 1-propenyl, butenyl or pentenyl.
• linear or branched alkynyl of 2 to 6 carbons includes ethynyl, propargyl, butynyl or pentynyl.
• linear or branched alkoxy of 1 to 6 carbons includes preferably methoxy or ethoxy but can also be a linear, secondary or tertiary propoxy, isopropoxy or butoxy.
• acyl of 1 to 7 carbons preferably includes formyl, acetyl, propionyl or benzoyl and acyloxy of 1 to 7 carbons encompasses acyl of one of the groups named above.
• the carbocylics such as cycloalkyl and the alkyl, alkenyl alkynyl or alkyloxy groups can be substituted with at least one substituent selected from the group consisting of halogen, such as chloro or bromo as in 2-bromoethyl; hydroxy; alkyl; alkenyl; alkynyl; aryl such as phenyl or naphthyl; aralkyl such as benzyl or phenethyl; cycloalkyl such as cyclopropyl, cyclopentyl or cyclohexyl; alkoxy such as methoxy, ethoxy propoxy or isopropoxy or methoxymethyl or 1-ethoxyethyl; aryloxy such as phenoxy; aralkyloxy such as benzyloxy; mercapto; alkylthio such as methylthio or ethylthio; arylthio, aralkyl
• R 1 and R 2 combine with the nitrogen atom to which they are attached to form a heterocycle, it is preferably pyrrolidino, piperidino, morpholino or piperazinyl.
• the second nitrogen atom that can be contained in the heterocycle formed by R 1 and R 2 can be substituted, for example, by a linear or branched alkyl or alkoxy of 1 to 5 carbon atoms, phenyl or benzyl optionally substituted by the substituents already mentioned above for aryl and aralkyl.
• halogen preferably is chlorine, but can also be fluorine, bromine or iodine.
• monoalkyl- or dialkylamino preferably is monoalkyl- or dialkylamino in which the alkyl contains 1 to 5 carbon atoms and especially methyl, ethyl or isopropyl.
• acyl of 2 to 6 carbon atoms preferably is acetyl, propionyl, butyryl or benzoyl but also includes valeryl, hexanoyl, acryloxyl, crotonoyl or carbamoyl.
• esterified carboxy preferably includes lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl or benzyloxycarbonyl and the substituted carbamoyl radical includes lower N-monoalkyl carbamoyl such as N-methylcarbamoyl, N-ethylcarbamoyl; a lower N,N-diethylcarbamoyl; an N-(lower hydroxyalkyl) carbamoyl such as N-(hydroxymethyl) carbamoyl, N-(hydroxyethyl) carbamoyl; and lower carbamoylalkyl such as carbamoylmethyl, carbamoylethyl.
• the substituted carbamoyl radical includes lower N-monoalkyl carbamoyl such as N-methylcarbamoyl, N-ethylcarbamoyl; a lower N,N-diethylcarbamoyl; an N-(low
• substituents that can be on the aryl, and more particularly the phenyl for R, Y and B cited, for example, are halogen such as chloro and bromo; hydroxy; alkyl such as methyl, ethyl, iso-propyl or tert-butyl; alkenyl; alkynyl; alkoxy, such as methoxy, ethoxy or isopropoxy; alkyl, alkenyl, alkynyl or alkoxy substituted by at least one member selected from the group consisting of hydroxy, linear or branched alkyl and alkoxy such as methyl, ethyl, tert-butyl, methoxy, ethoxy, isopropyl; substituted amino such as monoalkyl- and dialkylamino like methylamino, ethylamino or dimethylamino.
• the non-toxic, pharmaceutically acceptable acid addition salts may be salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid, organic acids such as propionic acid, acetic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid tartaric acid, citric acid oxalic acid, glyoxylic acid, aspartic acid, ascorbic acid.
• inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid
• organic acids such as propionic acid, acetic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid tartaric acid, citric acid oxalic acid, glyoxylic acid, aspartic acid, ascorbic acid.
• alkylmonosulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, alkyldisulfonic acids such as methanedisulfonic acid, alpha, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzensulfonic and the aryldisulfonic acids such as paratoluene sulphonic acid.
• the salts of bases can be salts of sodium, potassium, lithium, calcium, magnesium or ammonium, salts of organic bases such as methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris-(hydroxymethyl)-amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, porcaine, lysine, arginine, histidine or N-methylglucamine.
• organic bases such as methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris-(hydroxymethyl)-amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, porcaine, lysine, arginine, histidine or N-methylglucamine.
• A is a substituted cycloalkyl
• the products in which the substituents are in the trans position are preferred.
• substituents carried by aryl, aralkyl and heterocyclics or those that can be formed by R 1 and R 2 with the nitrogen atom to which they are attached are selected from the group consisting of halogen, alkyl, alkenyl, alkynyl or alkoxy of at most 7 carbon atoms and optionally substituted hydroxy, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, cyano, nitro, sulfamoyl, amino, monoalkyl and dialkylamino, formyl, acyl of 2 to 6 carbon atoms, and benzoyl, free carboxy or esterified by alkyl of 1 to 5 carbon atoms and salified, carbamoyl optionally substituted by at least one member selected from the group consisting of alkyl, alkoxy, hydroxyalkyl and carbamoylalkyl, the alkyl and alkoxy having 1 to 4 carbon atoms
• substituents carried on alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclic and alkyloxy are selected from the group consisting of halogen, alkyl, alkenyl, alkynyl or alkoxy of at most 5 carbon atoms, formyl, acyl of 2 to 6 carbon atoms and benzoyl, free carboxy or esterified with alkyl of 1 to 5 carbon atoms.
• R is alkyl, alkenyl and alkynyl optionally substituted with optionally substituted phenyl
• Y is phenyl, naphthyl, thionaphthyl, benzofuryl, benzopyrrolyl or indenyl optionally substituted by at least one member selected from the group consisting of halogen, alkyl, alkenyl, alkynyl or alkoxy of at most 7 carbon atoms optionally substituted by at least one member selected from the group consisting of hydroxy and alkyl and alkyloxy of 1 to 5 carbon atoms, acyl of 2 to 6 carbon atoms, trifluoromethyl, cyano, nitro, amino, monoalkyl- and dialkylamino of 1 to 5 carbon atoms, and phenyl optionally substituted by at least one member of the group consisting of halogen, hydroxy, cyano, nitro, alkyl, alken
• novel process of the invention for the preparation of the products of formula I comprises reacting a diamine of the formula: ##STR18## have the above meanings for ##STR19## or those in which the reactive functions that can be carried by ##STR20## are protected with an acrylic ester of the formula
• R 3 is alkyl of 1 to 6 carbon atoms to obtain condensed product of the formula ##STR21## and R 3 have the above meanings, reacting the latter with a compound of the formula ##STR22## in which R' is hydrogen or the values of R indicated above or those in which the reactive functions are protected, M is hydroxyl or halogen and Y' has the values of Y indicated above, or those in which the reactive functions are protected to obtain a product of the formula: ##STR23##
• R', R 3 and Y' have the above meanings corresponding to the case where R' is hydrogen or the values of R and A', NR' 1 R' 2 and Y' are respectively the values of A, NR 1 R 2 and Y, to form a product of formula I B as defined above, product of formula VI in which if appropriate, the protective groups are eliminated to obtain the same product of formula I B or which is optionally subjected to a cyclization reaction to obtain a product of the formula ##STR24## R' and Y'
• the condensation reaction of the distance of formula II with an acrylic ester of formula III in which R 3 is alkyl such as ethyl or methyl acrylate but which can also be butyl acrylate can be carried out in a solvent such as an alcohol like ethanol, methanol or butanol.
• a solvent such as an alcohol like ethanol, methanol or butanol.
• the solution can be cooled to a temperature of about 10° C. then left to return to ambient temperature with stirring so that the addition reaction forming the product of formula IV takes place.
• the acylation of the secondary amine of formula IV can be carried out by known methods for example, by the acid of formula V in which M is hydroxy in the presence of N,N'-carbonyldiimidazole or cyclohexylcarbodiimide or by the acid halide of formula V in which M is halogen such as chlorine.
• the reaction according to commonly used processes takes place in an organic solvent such as tetrahydrofuran or a chlorinated solvent such as methylene chloride with stirring at ambient temperature.
• the cyclization reaction of the product of formula VI into the corresponding product of formula VII can be carried out in a basic medium such as sodium or potassium hydride or an alcoholate such as potassium or sodium terbutylate in an organic solvent such as tetrahydrofuran, toluene or ether.
• the reaction medium can first be slowly cooled to a temperature of 12° C. to 15° C. then taken to ambient temperature or heated at reflux.
• the reduction of the product of formula VII or I A1 into the product of formula VIII or I A2 can be effected by the conversion of the oxo function of the formula VII into hydrazone by a reagent such as an arylsulfonyl hydrazine such as p-toluenesulfonyl hydrazine in an organic solvent such as acetic acid or an alcohol such as methanol or ethanol at ambient temperature.
• the reduced product of formula VIII can be obtained by decomposition of the intermediate hydrazone, the decomposition being carried out by sodium or potassium alcoholate such as sodium ethylate or sodium or potassium methylate or butylate.
• the reaction is carried out in a hydroxylated solvent such as hot ethylene glycol at a temperature of approximately 120° C. to 160° C.
• the reduction reaction of the product of formula VIII or I A2 into a product of formula IX or I A3 can be carried out by catalytic hydrogenation of the ethylene function in the presence of a hydracid such as hydrochloric acid or hydrobromic acid.
• the reaction is carried out in an alcohol such as ethanol in acetic acid or in an acid ester such as ethyl acetate, on platinum oxide at ambient temperature.
• the reduction reaction of the product of formula VIII into the product of formula IX can also be carried out by the action of a mixed hydride, for example, sodium borohydride in an organic solvent, for example, a lower alcohol, preferably ethanol.
• the strong base used is preferably an alkaline alcoholate i.e. potassium terbutylate.
• the agent capable of grafting R' onto the product of formula IX or I A3 can be an alkyl sulfonate but is preferably a halide.
• the alkyl sulfonate can be a mesylate but is preferably tosylate.
• the halide can be a chloride but is preferably a bromide or an iodide.
• the various reactive functions that can, if necessary, be protected by appropriate protective groups are, for example, hydroxyl, acyl, free carboxy and amino and monoalkylamino.
• the following non-exhaustive list of examples of protection of reactive functions can be cited:
• the hydroxy can be protected by trimethylsilyl, dihydropyran, benzyl, ethoxy or methoxymethyl and the aminos can be protected by trityl, benzyl, terbutoxycarbonyl, phthalimide or other groups known in the chemistry of peptides.
• the acyl such as formyl can be produced in the form of cyclic or non-cyclic ketals such as dimethyl- or diethylketal or ethylene dioxyketal and the carboxy groups can be protected in the form of esters formed with easily cleavable esters such as benzyl or terbutyl esters or esters known in the chemistry of the peptides.
• a subject of the invention is a preparation process for products of formula I as defined above, characterized in that the starting process of the products of formula IV as defined above is implemented and the process as indicated above is carried out.
• the optically active forms of the products of formula I can be prepared by resolution of the racemics according to the usual methods.
• novel central analgesic compositions of the invention are comprised of a central analgesically effective amount of at least one compound of formula I and its non-toxic, pharmaceutically acceptable salts with acids or bases and an inert pharmaceutical carrier.
• the compositions may be in the form of tablets, dragees, capsules, granules, suppositories, injectable solutions or suspensions, ointments, creams, gels and aerosol preparations.
• talc gum arabic, lactose, starch, magnesium stearate, coca butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, and preservatives.
• compositions show a strong affinity for opiate receptors and notably for the kappa receptors and are endowed with central analgesic properties. They are also endowed with diuretic properties, anti-arythmic properties, cerebral anti-ischemic properties and hypertensive properties.
• compositions are useful for the relief of pain of whatever origin, for example, pain of muscular, articular or nervous nature. They are also useful in the treatment of toothaches, migraines, shingles, in the treatment of intense pains, especially those resistant to peripheral analogesics, for example in the course of the neoplasia process, in the treatment of pancreatitis, nephretic or biliary colics, in the treatment of post-operative and post-traumatic pain. They can also be used in the treatment of cerebral deficiencies of an ischemic origin, and in disorders of memory and concentration.
• the novel method of the invention for relieving pain in warm-blooded animals, including humans comprises administering to warm-blooded animals an analgesically effective amount of at least one compound of formula I and its non-toxic, pharmaceutically acceptable salts with acids or bases.
• the compounds may be administered bucally, rectally, parenterally or topically to the skin or mucous membranes.
• the usual daily dose is 0.0666 to 5.333 mg/kg depending on the specific condition treated, the specific compound and the method of administration.
• the products of formula II in which A is carbocyclic can be prepared from commercially available benzylamine which is reacted with cyclohexyl oxide in an aqueous medium to obtain a compound of the formula: ##STR37## reacting the latter with chlorosulfonic acid in the presence of methylene chloride to obtain the sulfated derivative of the formula: ##STR38## which is reacted with sodium hydroxide in an aqueous medium to obtain the corresponding aziridine of the formula: ##STR39## which is reacted in the presence of ammonium chloride with the amine of the formula: ##STR40## in which R 1 and R 2 have the above meanings, to obtain the compound of the formula: ##STR41## which is debenzylated by catalytic hydrogenation to obtain the corresponding product of formula II,
• the other starting products of formula II can be prepared by comparable methods known to the ordinarily skilled artisan.
• the invention also relates to, as new industrial products, the compounds of formulae IV, VI, VII, VIII, IX and X.
• a mixture of 10.65 g of 3,4-dichlorophenyl acetic acid, 8.40 g of carbonyldiimidazole and 70 cm 3 of anhydrous tetrahydrofuran are agitated for 1 hour at ambient temperature.
• a solution of 12.65 g of the amine obtained in Stage A in 70 cm 3 of anhydrous tetrahydrofuran is added over 10 minutes. Agitation takes place for 5 hours at ambient temperature. Extraction takes place with ethyl acetate, followed by washing with 120 cm 3 of a saturated solution of sodium bicarbonate than twice with 70 cm 3 of water, drying and concentrating to dryness under reduced pressure.
• the residue 22 g is chromatographed on silica (eluent; ethyl acetate--triethylamine (97-3)). 17.6 g of expected product is obtained and is used as it is for the following stage:
• a mixture of 5 g of the base obtained in Example 2, 2.95 g of paratoluene sulphonyl hydrazide and 25 cm 3 of acetic acid are agitated for 4 hours at ambient temperature.
• 150 cm 3 of water saturated with sodium chloride is added to the reaction medium, then 50 cm 3 of sulphuric ether is added, and agitation takes place for 2 hours at ambient temperature.
• After separating, the whole is washed with 20 cm 3 of water saturated with sodium chloride and 5 cm 3 of sulphuric ether, then with a solution of potassium carbonate at 15% with water and with ether.
• M.p. approx. 200° C., which is used as it is for the following stage.
• 0.65 g of sodium is introduced over 30 minutes at 20° to 35° C. into 28 cm 3 of ethanol 100, then heated to 60° C. and 5.64 g of the product obtained in Stage A and 22 cm 3 of ethylene glycol are added.
• the ethanol is distilled off at standard pressure then heating takes place for 30 minutes to 160° C. in the reaction medium until no more gas is released.
• the extracts are dried, filtered and concentrated to dryness under reduced pressure, 3.78 g of product is collected in the form of the base.
• 1.319 g of the base obtained is chromatographed on silica (eluant : ethyl acetate with 0.5% triethylamine).
• the residue is taken up in 10 cm 3 of water and 50 cm 3 of ethyl acetate, alkalinization is carried out using an excess sodium carbonate followed by decantation, the aqueous phase is reextracted with 30 cm 3 of ethyl acetate, the organic extracts are washed with salt water, then dried, filtered and brought to dryness under reduced pressure.
• Example 2 The operation is carried out as in Example 2 starting with 5.2 g of the product obtained in Example 6.
• the product is isolated by taking up the dry extract obtained after evaporation under reduced pressure with water saturated with sodium chloride, followed by separating, washing with hexane and drying under reduced pressure.
• the filtrate is chromatographed again and 1.85 g of residue is thus collected which is united with the 0.538 g above to prepare the fumarate in the ethanol which is then crystallized from isopropanol, 1.419 g of fumarate obtained above is returned to the base, by displacement with sodium bicarbonate and sodium carbonate.
• the dry extract 1.050 g is dissolved in tetrahydrofuran at 50° C. and 423 mg of dihydrated oxalic acid is added and heated under reflux.
• a paste is made with 3.556 g of isomer A obtained in Example 9 in 10 cm 3 of sulphuric ether under reflux. 3.31 g of expected product is obtained in the form of a base.
• Example 4 The operation is carried out as in Example 4 starting with 5.4 g of the product obtained in Example 13, using 0.6 g of 80% platinum oxide and by hydrogenating under a pressure of 1500 mbars, 400 cm 3 of hydrogen is absorbed, 5.81 g of expected product is obtained which is chromatographed on silica (eluant; ethyl acetate with 2% triethylamine). 0.975 g of isomer A and 1.80 g of isomer B of the expected product are obtained.
• Example 14 1.75 g of the product obtained in Example 14 (isomer B) is dissolved in 8 cm 3 of isopropanol and 490 mg of fumaric acid is added, heating takes place until dissolution, followed by cooling to 20° C. separating, washing in isopropanol at 5° C. then with ether. 1.594 g of product is obtained which is recrystallized from 6 cm 3 of ethanol 100.
• Example 2 The operation takes place as Example 2 starting with 9.42 g of the product obtained in Example 16 using 1.15 g of sodium hydride. 9.35 g of expected product is obtained which is used as it is for the following example.
• Neutralization takes place by the addition of 8 cm 3 of an acetic acid--water mixture (1-1).
• the solvent is distilled off under reduced pressure, the residue is taken up with 50 cm 3 of ethyl acetate, 30 cm 3 of 20% sodium carbonate and 20 cm 3 of water.
• EXAMPLE 20 Fumarate of (S)-1-[1-phenyl-2-(1-pyrrolidinyl)-ethyl]-3-(4-trifluoromethyl)-phenyl)-2-piperidinone (isomer A and isomer B) and the fumarate of isomer B
• EXAMPLE 21 Ethyl (S)-3-(((3,4-dichlorophenyl)-acetyl)-1-(2-methyl-1-((1-pyrrolidinyl)-methyl)-propyl)-amino)propanoate
• Stage B of Example 1 The operation is carried out as Stage B of Example 1 starting with 28.7 g of 3,4-dichlorophenylacetic acid, 27.52 g of the product obtained in Stage A and 22.7 g of carbonyldiimidazol, 57.2 g of crude product is obtained which is purified by chromatography on silica (eluant : ethyl acetate-methanol (95-5) and 39.2 g of expected product is obtained.
• a mixture containing 42.88 g of the product obtained in Stage A in 429 cm 3 of ethanol and 17 cm 3 of hydrochloric acid in the presence of 4.22 g of activated charcoal with 10% of palladium has a stream of hydrogen under 1880 mbars passed through it for 3 hours. After filtering, the filtrate is concentrated under reduced pressure. Crystallization is started, the residue is taken up with 50 cm 3 of ethyl acetate, the expected product crystals are separated in the form of the hydrochloride, they are dissolved in 25 cm 3 of water and 25 cm 3 of caustic soda lye is added. Extraction takes place with methylene chloride, followed by drying and eliminating the solvent under reduced pressure. 19.79 g of expected product is obtained which is used as it is for the following stage.
• Example 2 The operation is carried out as in Example 2 starting with 16.71 g of the product obtained in Example 21 using 2.76 g of sodium hydride. 13.37 g of expected product is obtained which is used as it is for the following example.
• 17 g of the product obtained above is taken up in 100 cm 3 of ethyl acetate and 20 cm 3 of water and 2.5 g of sodium carbonate are slowly added. After agitating, decanting, extracting with ethyl acetate, washing with salt water, drying and eliminating the solvents under reduced pressure, 5.54 g of expected product is obtained in the form on the base.
• Example 19 The operation is carried out as in Example 19 starting with 3.25 g of the base obtained in Example 23 and 0.77 g of sodium borohydride and 3.17 g of crude product is obtained. After chromatography, 1.44 g of isomer A and 1.37 g of isomer B are obtained.
• Example 2 The operation is carried out as in Example 2 starting with 7.955 g of the product obtained in Example 26 and 1.12 g of sodium hydride.
• Example 19 The operation is carried out as in Example 19 starting with 2.66 g of product obtained in Example 28 and 0.62 g of sodium borohydride. 2.7 g of crude product is obtained. After chromatography, 1.59 g of isomer A and 1.05 g of isomer B are collected.
• Example 20 The operation is carried out as in Example 20 starting with 9.81 mg of isomer B prepared in Example 29 and 325 mg of fumaric acid. 1.07 g of the expected fumarate is obtained.
• Example 2 The operation is carried out as in Example 2 starting with 9.47 g of the product obtained in Example 31 using 1.15 g of sodium hydride. 10.45 g of expected product is obtained which is used as it is for the following example.
• Example 19 The operation is carried out as in Example 19 starting with 4.93 g of product obtained in Example 33 and 3 times 1 g of sodium borohydride. 5.23 g of crude product is obtained. After chromatography, 2.64 g of isomer A and 2.07 g of isomer are collected.
• Example 36 The operation is carried out as in Example 36 starting with 2 g of the product obtained in Example 14, 0.87 g of potassium terbutylate and 0.6 cm 3 of ethyl iodide. 2.1 g of crude product is obtained the form of the base which is chromatographed on silica (eluant : ethyl acetate-methylene chloride (85-15)).
• Example 36 The operation is carried out as in Example 36 starting with 2.76 g of product obtained in Example 14, 0.98 g of potassium terbutylate and 1.2 cm 3 of benzyl bromide. 3.22 g of expected product is obtained in the form of the base. After chromatography on silica (eluant : ethyl acetate--methyl chloride (75-15)), 668 mg of isomer A and 553 mg of isomer B are obtained.
• Example 37 The operation is carried out as in Example 37 starting with 455 mg of isomer B dissolved in 5 cm 3 of isopropanol and 110 mg of fumaric acid. 350 mg of the expected fumarate is obtained.
• Example 40 462 mg of isomer A base obtained in Example 40 is dissolved in 4.5 cm 3 of ethanol at ambient temperature and 0.5 cm 3 of a 6.6N ethanolic solution of hydrogen chloride is added. Crystallization is started, followed by separating and drying the crystals at 80° C. under reduced pressure and 340 mg of the expected hydrochloride is collected.
• Example 36 The operation is carried out as in Example 36 starting with 2.01 g of the product obtained in Example 14, 0.9 g of potassium terbutylate and 0.65 cm 3 of allyl bromide. 2.28 g of expected crude product is obtained in the form of the base. After chromatography on silica (eluant : ethyl acetate --methylene chloride--n-hexane (3-4-3)) 868 mg of isomer A and 940 mg of isomer B are obtained.
• silica eluant : ethyl acetate --methylene chloride--n-hexane (3-4-3)
• Example 38 The operation is carried out as in Example 38 starting with 913 mg of isomer B, obtained in Example 42 and 1.2 cm 3 of a (2M) ethanolic solution of methane sulphonic acid and 780 mg of the expected methanesulphonate is obtained.
• M.p. 239°-241° C.
• Membrane samples preserved at -30° C. (optionally for approximately 30 days) are used and prepared from guinea pig brains.
• the non-specific bond is determined by the addition of known product under the name U-50488 H (Lahti et al. 1982, Life Sci. 31, 2257) at 10 -5 M (in triplicate). After incubating at 25° C. for 40 minutes, returning to the water bath at 0° C. for 5 minutes, filtering under vacuum, rinsing with Tris pH 7.7 buffer, the radioactivity is counted in the presence of Trition scintillator.
• IC 50 50% inhibiting concentration
• needles are implanted subcutaneously so as to record the rats' electrocardiogram on the DII derivation signal.
• test products are administered by intravenous route. Five minutes after administration of the product, the jugular vein is perfused with aconitine at the rate of 10 micrograms/mn and the time taken for the appearance of cardiac rhythm disorders is noted.
• results are expressed as a percentage of the increase in the time taken for cardiac rhythm disorders to appear relative to the controls and according to the dose of the test product.

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